Advanced age has been shown to be a factor predicting poor survival in patients with brain metastases (BM). There have been only a few studies focusing on stereotactic radiosurgery (SRS) for elderly BM patients. The present study aimed to investigate the efficacy and limitations of SRS for very elderly BM patients.
Trang 1R E S E A R C H A R T I C L E Open Access
Is upfront stereotactic radiosurgery a
rational treatment option for very elderly
patients with brain metastases? A
retrospective analysis of 106 consecutive
patients age 80 years and older
Shoji Yomo1,2*and Motohiro Hayashi2
Abstract
Background: Advanced age has been shown to be a factor predicting poor survival in patients with brain
metastases (BM) There have been only a few studies focusing on stereotactic radiosurgery (SRS) for elderly BM patients The present study aimed to investigate the efficacy and limitations of SRS for very elderly BM patients Methods: This was a retrospective observational study analyzing 106 consecutive patients (69 males/37 females) age 80 years and older who received upfront Gamma Knife SRS for BM between January 2009 and October 2015 The median age was 84 years, and the median Karnofsky performance status (KPS) was 70 Fifty-two patients had a solitary BM, and others multiple BM The median cumulative tumor volume was 3.9 mL and the median dose prescribed was 20 Gy Overall survival (OS), neurological death rates and distant and local intracranial tumor control rates were analyzed
Results: No patients were lost to follow-up Six-month and 12-month OS rates were 54% and 32%, respectively The median OS time was 7.1 months Competing risks analysis showed that 6-month and 12-month neurological death rates were 8% and 11%, respectively In total, 245 / 311 tumors (79%) in 82 patients (77%) with sufficient radiological follow-up data were evaluated Six-month and 12-month distant BM recurrence rates (per patient) after SRS were 17% and 25%, respectively Six-month and 12-month rates of local tumor control (per lesion) were 94% and 89%, respectively Repeat SRS, salvage WBRT and surgical resection were subsequently required in 25, 4 and 1 patient, respectively Proportional hazard regression analysis showed that KPS≥ 70 (HR: 0.444, P < 001), controlled primary disease/no extracranial metastases (HR: 0.361,P < 001) and female sex (HR: 0.569, P = 0.028) were independent factors predicting better OS Similarly, tumor volume (>2 mL) was the only factor predicting a higher rate of local control failure (HR: 12.8,P = 0.003)
Conclusions: The present study suggested an upfront SRS strategy to offer a feasible and effective treatment option for very elderly patients with limited BM In the majority of patients, neurological death could be delayed
or even prevented
Keywords: Brain metastases, Elderly patients, Stereotactic radiosurgery, Gamma knife
* Correspondence: yomoshoji@gmail.com
1
Division of Radiation Oncology, Aizawa Comprehensive Cancer Center,
Aizawa Hospital, 2-5-1, Honjo, Matsumoto-city, Nagano-prefecture 390-0814,
Japan
2 Saitama Gamma Knife Center, San-ai Hospital, Saitama-city,
Saitama-prefecture, Japan
© The Author(s) 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 2In industrial nations, demographic projections portend a
substantial increase in numbers of older persons, thus
im-plying consequent increases in cancer incidence and
mor-tality in the elderly [1] Advanced age has been shown to
be an important prognostic factor for survival in patients
with brain metastases (BM) [2–6] Diminished
per-formance status and the presence of co-morbidities
may make radiotherapy less feasible in the elderly
Moreover, elderly patients may prefer less aggressive
treatment for BM In fact, palliative whole brain
radio-therapy (WBRT) utilization rates drop steeply in the
elderly [7] Recently, in selected patients, WBRT has
been omitted from the initial management for BM with
the aim of reducing the potential risk of delayed
neuro-logical toxicity [8–10] Stereotactic radiosurgery (SRS)
has emerged as the preferred treatment modality, either
alone or in combination with other modalities [10, 11]
The delivery of highly focused radiation with a sharp dose
fall-off is theoretically expected to reduce delayed
neuro-toxicity, and this feature makes it applicable in both the
upfront and the salvage setting To date, a few studies
have investigated SRS treatment results for elderly patients
with BM, but the definitions of elderly patients differed
among these prior SRS studies (Table 1) [12–16] We
con-sider evidence for the clinical efficacy of SRS for elderly
patients with BM to still be insufficient and advocate
add-itional research to confirm the therapeutic benefits of SRS
in this population
Thus, the efficacy and limitations of our SRS-oriented
treatment strategy for very elderly patients, i.e those at
least 80 years of age, with newly diagnosed and/or
recur-rent BM were investigated The present study also
ex-plored factors predicting the survival of elderly patients
undergoing SRS
Methods
Patient population
The present study was conducted in compliance with the Declaration of Helsinki (sixth revision, 2008), and fulfilled all of the requirements for patient anonymity The Aizawa Hospital Institutional Review Board ap-proved this retrospective clinical study in October 2015 (No 2015–038)
We analyzed our prospectively maintained institu-tional radiosurgical database to examine the radio-logical and clinical outcomes Between December 2008 and October 2015, 106 consecutive very elderly patients with BM who underwent Gamma Knife SRS as upfront treatment were eligible for the present study During this study period, 2 patients receiving prior WBRT be-fore SRS were identified and excluded Of the eligible patients, 69 were male and 37 were female The median age was 84 years (range: 80–93 years) The median Karnofsky performance status (KPS) at the time of SRS was 70 (range: 30–100) The primary cancers were of the lung in 74 patients (including 8 with small cell lung cancer), the digestive tract in 16, melanoma in 3, the breast in 2, the kidney in 2, the thyroid in 2, the ovary
in 1, and were of unknown origin in 6 patients Before SRS, 7 patients had undergone microsurgical resection
of BM and one had received an endoscopic third ventri-culostomy for obstructive hydrocephalus The median interval between primary diagnosis and SRS was 11.3 months (range: 0–246 months) Patient character-istics are summarized in Table 2
Radiosurgical Indications and Techniques
One hundred and three (97%) patients included in the present study had been diagnosed and their primary tu-mors treated at the referring regional hospitals, whose
Table 1 Series of treatment outcomes of elderly patients undergoing SRS for BM
First author
& year
Treatment
modality
No of patients
Median age (Cut-off age)
No receiving prior WBRT (%)
MST after SRS (months)
Factors predicting longer OS
Local tumor control
Remote brain recurrence
91%/2 years
33%/
6 months 60%/2 years
( ≥75 years) 17 (39%)
Minniti, 2013
[14]
( ≥70 years) 0 (0%) 13.2 KPS > 70, Stableextracranial disease
90%/1 year 84%/2 years
54%/1 year 78%/2 years Watanabe,
2014 [15]
b
( ≥70 years) 13 (9%) 5.6 KPSNo extracranial metastasis≥ 90,
Present study,
2016
( ≥80 years) 0 (0%) 7.1 KPSprimary/no extracranial≥ 70, Controlled
metastasis, Female sex
94%/
6 months 89%/1 year
17%/
6 months 25%/1 year
SRS stereotactic radiosurgery, BM brain metastasis, WBRT whole brain radiotherapy, MST median survival time, LINAC linear accelerator, GK gamma knife, a
time b
Trang 3own cancer boards had provisionally determined the
ap-propriateness of SRS The patients were then referred to
our institution to receive SRS for BM The remaining
three patients had been treated at our institution The
SRS protocol used in this study was based on the
stand-ard care established at our institution Patients with up
to ten BM principally received SRS Providing that
WBRT had been refused by the patient, SRS was applied
for multiple BM, even in cases with more than 10
le-sions, when the patient’s systemic condition was such
that SRS intervention would be tolerable and fully
informed consent for treatment had been obtained
Surgical resection was, in principle, indicated for large
tumors with a mass effect If surgery did not seem
feas-ible due to a poor prognosis or advanced systemic
dis-ease, 2-session SRS was indicated for carefully selected
large tumors (≥10 mL) [17]
SRS was performed using the Leksell G stereotactic frame
(Elekta Instruments, Stockholm, Sweden) The frame was
placed on the patient’s head under local anesthesia
supple-mented with mild sedation Three-dimensional volumetric
gadolinium-enhanced T1-weighted magnetic resonance
(MR) images, 2 mm in thickness, T2-weighted MR
im-ages and contrast-enhanced computed tomography
covering the whole brain were routinely used to
gener-ate a treatment plan with Leksell Gamma Plan software
(Elekta Instruments) Prescribed doses were selected in
principle according to the dose protocol of the JLGK
0901 study [10] The technical details of 2-session SRS
were previously described in detail [17] Total
prescrip-tion doses in 2-session SRS were recalculated into a
single dose applying a linear-quadratic (LQ) model by
assuming the alpha/beta ratio to be 10 for BM [18] All
treatments were performed with the Leksell Gamma Knife Model C or Perfexion
Post-SRS Management and Follow-up Evaluation
Clinical follow-up data as well as contrast-enhanced MR images were obtained every one to three months If metachronous distant metastases were identified, they were, in principle, managed with repeat SRS When mil-iary metastases (numerous tiny enhanced lesions) and/or leptomeningeal carcinomatosis was newly documented, WBRT was then recommended Local control failure was defined as an at least 20% increase in the diameter
of the targeted lesions, taking as a reference the pre-SRS diameter, irrespective of whether the lesion was a true recurrence or delayed radiation injury We endeavored
to meticulously differentiate delayed radiation injury from tumor recurrence, based on serial MR imaging findings [19] and the clinical course Additional SRS was possible provided that the volume of the local tumor re-currence was small enough for single-dose SRS Surgical removal was indicated when neurological signs became refractory to conservative management, regardless of whether the radiological diagnosis was local tumor pro-gression or radiation necrosis Any adverse events attrib-utable to SRS procedures were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE; ver.4.0)
Before closing the research database for analysis in August 2016, the authors updated the follow-up data of patients who had not visited our outpatient department for more than three months Inquiries about the date and mode of death were made by directly corresponding with the referring physician and/or the family of the de-ceased patient, with written permission obtained at the time of undertaking SRS from all patients and/or their relatives, allowing the use of personal data for clinical re-search Neurological death was defined as death attribut-able to central nervous system metastases including tumor recurrence and carcinomatous meningitis Deaths with unspecified causes were also categorized as neuro-logical deaths in the present study
Statistical analysis
The overall survival (OS) rate was calculated by the Kaplan-Meier product limit method The neurological and non-neurological death rates were calculated employing Gray’s test [20], wherein each event was regarded as a competing risk for another event For the estimation of local control failure rates and distant BM recurrence, Gray’s test was similarly applied, with subse-quent WBRT for distant recurrence and the patient’s death being regarded as competing events, respectively All of the above analyses were based on the interval from the date of initial SRS treatment until the date of
Table 2 Summary of clinical data from 106 consecutive patients
( n = 106)
Controlled primary disease and no extracranial
metastases
25 (24%)
Time from primary diagnosis to initial
SRS (months), median (range)
11.3 (0 –246) Cumulative TV on initial SRS (mL), median
(range)
3.9 (0.2 –53.3)
No of intracranial lesions at initial SRS, median (range) 2 (1 –16)
No of patients treated with 2-session SRS 15 (14%)
KPS Karnofsky performance status, RTOG radiation treatment oncology group,
RPA recursive partitioning analysis, SRS stereotactic radiosurgery, TV
tumor volume
Trang 4each event The Cox and Fine-Gray proportional hazards
models [21] were appropriately employed to investigate
prognostic factors associated with OS and neurological
death-free survival, and for local tumor control Potential
prognostic factors were selected with reference to other
SRS series [12–14, 16, 22, 23] The statistical processing
software package“R” version 3.0.1 (The R Foundation for
Statistical Computing, Vienna, Austria) was used for all
statistical analyses AP-value < 0.05 was considered to
in-dicate a statistically significant difference
Results
Eighty-one patients (76%) had active systemic disease
and/or extracranial metastases and 31 (29%) were
receiv-ing systemic chemotherapy around the time of the initial
SRS Sixteen patients (15%) received molecular targeted
therapy, and 12 patients with epidermal growth factor
mutation positive lung adenocarcinoma were
adminis-tered oral tyrosine kinase inhibitors Fifty-two patients
(49%) had solitary BM The median number of BM at
the initial SRS was 2 (range: 1–16 tumors) In total, 311
tumors were being treated at the time of the initial SRS
The median tumor volume (TV) was 0.4 mL (range:
0.01–53.3 mL) and the median cumulative TV was
3.9 mL (range: 0.2–53.3 mL) The median prescribed
dose for single-session SRS was 20 Gy (range: 15–
22 Gy) Fifteen patients (14%) with 17 large tumors were
allocated to 2-session SRS The median TV of large BM
treated with 2-session SRS was 17.9 mL (range: 10.1–
53.3) and the median cumulative dose prescribed was
27 Gy (range: 20–28) By the time of the second session,
the median TV had been reduced to 8.6 mL (range: 2.3–
42.6)
Full clinical results were available for all 106 patients
as follow-up data had been completely updated in all
patients The median follow-up time after SRS was
7.1 months (range: 0.3–64 months) At the time of
as-sessment, 11 patients (10%) were alive and 95 (90%)
had died The cause of death in 77 patients was
pro-gressive systemic cancer or related complications (e.g.:
acute respiratory failure, liver insufficiency) and one
patient died from severe head trauma not associated
with either the systemic cancer or BM Eleven patients
died as a consequence of their BM and in the
remaining 6 the cause of death could not be specified
The median survival time (MST) was 7.1 months (95%
CI: 4.6–8.7) Six-month and 12-month OS rates after
SRS were 54% and 32%, respectively (Fig 1) Eleven of
these 106 (10%) elderly patients survived more than
2 years after SRS The Cox proportional hazards model
for OS identified KPS≥ 70 (Hazard ratio (HR): 0.444,
95% confidence interval (CI): 0.284–0.715, P < 001)
(Fig 2a), controlled primary and no extracranial
me-tastasis (HR: 0.361, 95% CI: 0.206–0.632, P < 001)
(Fig 2b) and female sex (HR: 0.569, 95% CI: 0.344– 0.942, P = 0.028) (Fig 2c) as favorable factors inde-pendently predicting better OS rates (Table 3) Six-month and 12-Six-month neurological death probabilities adjusted for competing events (non-neurological death) were 8% and 11%, respectively (Fig 1) No factors were identified as being statistically signifi-cantly associated with higher risk of neurological death by the Fine-Gray proportional hazards model (Table 4)
Only the 245/311 tumors (79%) in 82 patients (77%) who had sufficient radiological follow-up data were ana-lyzed herein because the other 24 patients died from sys-temic disease progression without follow-up MR imaging studies Distant metachronous BM were ob-served in 25 patients (24%) Six-month and 12-month distant BM recurrence rates (per patient) after SRS were 17% and 25%, respectively (Fig 3a) Six-month and 12-month local tumor control rates (per lesion) were 94% and 89%, respectively (Fig 3b) Fifteen BM were eventu-ally diagnosed as local tumor recurrence at a median time of 4.7 months after SRS (range: 3.4–12.8 months)
A sub-analysis of 2-session SRS conducted for large tu-mors found a durable TV reduction coupled with symp-tom relief for 14 of 17 tumors (82%) Three large tumors recurred after initially being responsive to SRS and sal-vage SRS was thus conducted between 4.7 months and 12.8 months after the initial treatment The proportional
Fig 1 Survival results for very elderly ( ≥80 years of age) patients with BM treated with SRS The solid line represents overall survival (OS) probability The median survival time (MST) was 7.1 months (95% CI: 4.6 –8.7) Six-month and 12-month OS rates after SRS were 54% and 31%, respectively The dotted line represents the neurological death-free survival (NS) probability adjusted for competing events Six-month and 12-month NS rates after SRS were 92% and 89%, respectively Note that the distance between these two lines, NS and
OS, represents the cumulative incidence of non-neurological death
Trang 5hazards model demonstrated TV larger than 2 mL (HR: 12.8, 95% CI: 2.32–69.3, P = 0.003) to be the only factor predicting a higher rate of local control failure (Table 5) (Fig 3c)
Twenty-five patients (24%) required repeat SRS for distant or local BM recurrence The total number of SRS sessions ranged up to 8 and the total number of BM treated per patient ranged up to 42 Four patients (4%) underwent salvage WBRT between 2.6 and 22.6 months after SRS because of subsequent development of miliary
BM and/or leptomeningeal dissemination One patient had to undergo surgical resection under a provisional diagnosis of symptomatic local recurrence 6.6 months after SRS and the histopathological diagnosis was radiation ne-crosis which predominated over viable adenocarcinoma Regarding adverse radiation effects, we experienced one case of radiation-induced optic nerve neuropathy (CTCAE grade 4), secondary to salvage SRS for meta-chronous recurrence around the left optic canal Prior to intervention, this patient had been informed of the pre-dicted risk to the affected optic nerve and consented to undergo the intervention Repeat seizures occurred and newly required anticonvulsive therapy in 3 patients (CTCAE grade 3) Two patients required prolonged oral steroids for delayed symptomatic radiation necrosis (CTCAE grade 2) Tumor-related hemorrhage was ob-served in 5 patients (3 melanomas, 1 lung adenocarcin-oma and 1 renal cell carcinadenocarcin-oma) and one of these was mildly symptomatic but eventually showed clinical and radiological stabilization (CTCAE grade 2)
Discussion
Current demographic changes as the rationale for the present study
Over the past few decades, the longest extension in life expectancy worldwide has been observed in Japan [24] World Health Statistics 2014 published by the WHO
Fig 2 Overall survival (OS) results stratified according to independent prognostic factors KPS ≥ 70 (Hazard ratio (HR): 0.444, P < 001) (a) Controlled primary disease/no extracranial metastases (HR: 0.361, P < 001) (b) Female sex (HR: 0.569, P = 0.028) (c)
Table 3 Analysis of factors predicting patient survival after SRS
(Cox proportional hazards model)
Covariate (No of patients) MST
(months)
P value Hazard ratio (95% CI)
Controlled systemic
disease/no extracranial
metastasis
< 001 0.361 (0.206 –0.632)
Interval from primary diagnosis
to SRS
0.053 0.687 (0.448 –1.05) Long > 12 months (54) 8.8
Short ≤ 12 months (52) 4.4
Large > 5 mL (61) 5.4
SRS stereotactic radiosurgery, MST median survival time, CI confidence interval,
KPS Karnofsky performance scale, PIV prescription isodose volume
Trang 6showed the life expectancies at birth of Japanese men
and women to both exceed 80 years [25] The definition
of elderly, when discussing patients with cancer, varies
In many previous studies of SRS for elderly patients with
BM, the cut-off ages were set between 65 and 75 years
(Table 1) [12–14, 16] In our country, cancer patients in
their 70s are no longer seen as the elderly requiring
spe-cial care and significant proportions of those age 80 years
and older still receive active anti-cancer treatments, as
described in the present study Together with advances
in the development of systemic treatments, the
long-term control of intracranial disease has become
increas-ingly important not only for overall disease control but
also for the patient’s quality of life However, it is not
uncommon for elderly patients to have multiple,
concur-rent diseases restricting their physiological reserves as
well as age-related cognitive decline [16] Elderly
pa-tients with cancer are, in general, less likely to receive
definitive therapy and their decisions about treatment may also be influenced by nonmedical, potentially cor-rectable factors such as impaired social services support for those receiving treatment [26]
Few, if any, studies have investigated SRS treatment re-sults for very elderly patients, i.e those at least 80 years
of age, with BM [15] and this aged population has been under-represented in clinical trials of cancer therapy, even in the era of targeted therapy Thus, the authors considered the age of 80 years to be a reasonable cut-off point, given that the present study aimed to investigate the efficacy and the limitations of comprehensive man-agement of SRS for BM in the very elderly patient population
Survival after SRS of elderly patients with BM
The MST slightly longer than 7 months demonstrated herein appears to be shorter than in previous studies of SRS series investigating different patient cohorts con-ducted in the authors’ institutions [23, 27, 28] This observation may support age being an important prog-nostic factor in the majority of patients with malignant primary or metastatic brain tumors, [2, 3] Watanabe et
al also demonstrated in their case-matched study that post-SRS MST was, in fact, slightly shorter in patients
80 years of age and older than in those 65–79 years of age, although the difference did not reach statistical sig-nificance The OS results after SRS in the present study seemed to be comparable to those of previous studies (Table 1) Minniti et al reported an exceptionally better
OS rate than in other studies This might be attribut-able to patient selection criteria such as their adoption
of an age cut-off of 70 years, oligometastases (1–4 BM), exclusion of small cell lung cancer, and so on The present study placed priority on generalizability by
Table 4 Analysis of factors predicting neurological death-free
survival after SRS (Fine-Gray proportional hazards model)
Controlled systemic
disease/no extracranial metastasis
0.62 1.35 (0.417 –4.35) Long interval from primary diagnosis
to SRS (>12 months)
0.48 1.41 (0.549 –3.60)
Small cumulative PIV ( ≤5 mL) 0.15 0.438 (0.144 –1.33)
SRS stereotactic radiosurgery, CI confidence interval, KPS Karnofsky
performance scale, PIV prescription isodose volume
Fig 3 Distant intracranial recurrence rate (a), overall local tumor control rate (b) and local tumor control rates stratified according to the tumor volume (TV) (c) Six-month and 12-month distant intracranial recurrence rates (per patient) were 17% and 25%, respectively Six-month and 12-month local tumor control rates (per lesion) were 94% and 89%, respectively TV larger than 2 mL was the only factor predicting a higher rate of local control failure (HR: 12.8, P = 0.003)
Trang 7including all consecutive cases, even those with large
multiple BM and/or very low KPS, and thus reflects the
contemporary situation of patients with BM in the
community
Prognostic factors and selection of candidates for SRS
among elderly patients with BM
Identifying factors predicting longer survival in patients
with BM is critically important for assigning patients to
the optimal treatment modality In our patient cohort,
higher KPS (≥70) (Fig 2a), controlled primary disease/
no extracranial metastases (Fig 2b) and female sex
(Fig 2c) were independently associated with better
pa-tient survival in multivariate analyses (Table 3) High
KPS scores and systemic disease control have already
been validated in large prospective datasets from
radi-ation therapy oncology group (RTOG) trials [2, 5], as
well as being reproduced in prior studies focusing on
elderly patients (Table 1) Regarding female sex, we
speculate that this might be attributable to the difference
in the prevalence of molecular targeted therapy use
between males and females In our patient cohort, 14 of
16 patients receiving molecular targeted therapy were
female Although not shown in the results because these
observations are quite preliminary, patients treated with
molecular targeted therapy had longer survival than
those not receiving such treatments (16.9 months vs
5.8 months, log-rank test,P = 0.007) The emerging role
of combining SRS and molecular targeted therapy merits
future investigation Our observations suggest that
se-lected subsets of patients can be expected to experience
prolonged survival, although the expected survival may
be limited in the majority of elderly patients with BM
The long interval from primary diagnosis to SRS was of
borderline significance in the multivariate analysis (P =
0.053) This might, at least in part, be attributable to
pa-tients with a long prior disease history having been
self-selected to do well by virtue of having had time to
de-velop BM and not dying of their systemic disease due to
inherently indolent cancers
The mode of death and its clinical significance
Concerning the cause of death, many of these patients
actually died of extracranial disease progression, as
demonstrated herein Given this observation, OS may not be an appropriate endpoint for accurately evaluating the efficacy and limitations of SRS for BM The authors believe it to be important to measure how SRS might delay or even prevent worsening neurological symptoms and eventually neurological death regardless of the pa-tient’s age, while adequately maintaining the papa-tient’s quality of life From this viewpoint, clinical information about the mode of death and the local control of BM is indispensable Understanding potential differences in the mode of death, is anticipated to facilitate answering the important question of whether treating BM delays neurological progression long enough to allow for a comfortable remaining life The present study showed that neurological death could be delayed or even pre-vented by SRS in the majority of very elderly patients with BM, although the observed OS was still limited Unfortunately, no risk factors clearly associated with neurological death were identified herein (Table 3), probably due to the lack of events of interest Further experience needs to be accumulated to identify factors potentially influencing neurological death
Importance of follow-up management and salvage treatment strategies
The local tumor control rate demonstrated herein ap-peared to be acceptable and was similar to those ob-tained in previous studies (Table 1) [12–15] Regarding factors influencing local tumor control in the present study, mid-size to large tumors (>2 mL) were more likely to recur or complicate radiation-induced toxic events (Table 4) This finding supports prior SRS stud-ies showing TV to be an important predictor of local control in patients with BM treated with single-dose SRS [22, 29, 30] The present study failed to demon-strate the relationship between prescription dose and local control rate We speculate that one of the reasons might involve the validity of dose estimation for 2-session SRS based on the LQ model, which is applied
to adjust for the difference between a single session and two sessions There has been controversy as to whether the LQ model is appropriate for large doses per frac-tion Brown et al recently reported that, for most tumors, the LQ model is still relevant for explaining the results obtained from clinical studies of SRS and stereotactic radiotherapy [31] On the other hand, the possibility of additional biological effects resulting from endothelial cell damage, enhanced tumor immunity, or both has been suggested [32, 33] However, we do not yet have an appropriate model taking into account these additional factors
Two-session SRS conducted for large tumors, in fact, achieved an acceptable local control rate (75% at 1 year) although it was lower than that of small metastases
Table 5 Analysis of factors predicting local tumor control failure
(Cox proportional hazards model)
Tumor causing focal deficit 0.379 1.69 (0.526 –5.41)
High marginal dose ( ≥20Gy) 0.949 1.04 (0.317 –3.41)
CI confidence interval, TV tumor volume, SRS stereotactic radiosurgery
Trang 8(Fig 3c) Considering the low alpha/beta ratio of the tissue
in the central nervous system and the author’s as yet
lim-ited experience, hypofractionated stereotactic radiotherapy
might be among the potential alternatives for reducing
acute toxicities while improving the local control rate in
patients with mid-size to large tumors However, the
clin-ical evidence accumulated to date is not yet conclusive
[34, 35] The potential for improvement of local tumor
control using hypofractionated stereotactic radiotherapy
with a Gamma Knife unit warrants further research
Subsequent intervention was actually needed in 26
patients (25%), mostly because of distant BM
recur-rence Most of these cases were successfully managed
with repeat SRS Hanssens et al reported that SRS
alone based on high-resolution MR imaging, decreased
the incidence of and increased the time until distant
re-currences [36] In fact, the competing risks regression
analysis employed herein indicated the rate of salvage
treatment for new BM to be somewhat lower than
those in prior studies (25% at 1 year) [12–14] Although
there is no general consensus regarding the risks and
benefits of omitting upfront WBRT, it appears that
re-peat radiosurgery may be effective as salvage therapy
for recurrent tumors after SRS alone, especially in
eld-erly patients Taking into account the detrimental
de-layed effects of WBRT on cognitive function and
health-related quality of life [8, 9, 37], it may be a
ra-tional treatment approach to strategically withhold
WBRT until it would presumably be the most efficient
treatment option [9] To assure the relevance of SRS
management, meticulous clinical and neuroimaging
follow-up and timely salvage SRS are essential, while it
should be noted that such a treatment strategy does
have the potential to place a major socio-economic
bur-den on elderly cancer patients and their relatives
Weaknesses of the present study
This study has several limitations The critical issue in
the present study is patient selection bias inherent to the
retrospective approach It is possible that elderly patients
with limited numbers of BM in the present study had
developed tolerance to the treatment and also had better
access to our institution and were consequently
self-selected to do well It must be also appreciated that we
cannot address the potential role of SRS in comparison
to WBRT, given the exploratory nature of the analyses in
a non-comparative study We could not control for the
possibility that there may have been patients not sent
to us, due to referral bias, whose outcomes could have
differed from what was observed in the present patient
cohort In follow-up management, some patients
con-tinued to be followed by their referring oncologists
Neuroimaging protocols could have differed among
these hospitals, and we cannot rule out the possibility
of patients not being referred to our institution even if tiny intracranial local or distant recurrences were de-tected in those in poor condition with very short life expectancies Therefore, it is necessary to fully recognize that the rates of local and distant recurrences of BM might
be underestimates In addition, the relatively small num-ber of patients and relative heterogeneity of the patient population may have limited the statistical power of the analyses, leading to incorrect conclusions More evidence-based information obtained from a well-designed prospective comparative study is needed to confirm our findings regarding the clinical efficacy of SRS for elderly patients with BM
Conclusions
We investigated the efficacy of SRS for BM in a cohort
of very elderly patients and our findings suggested SRS
to be a feasible and effective treatment option even for those of advanced age with BM Close follow-up and continuation of radiosurgical management might con-tribute to reducing the rate of neurological death Prog-nostic factors associated with better OS in our cohort were high KPS, controlled primary disease/no extracra-nial metastases and female sex
Abbreviations BM: brain metastases; CI: confidence interval; HR: hazard ratio; KPS: Karnofsky performance status; LQ: linear-quadratic; MR: magnetic resonance; MST: median survival time; NCI-CTCAE: national cancer institute common terminology criteria for adverse events; OS: overall survival; PIV: prescription isodose volume; RPA: recursive partitioning analysis; RTOG: radiation treatment oncology group; SRS: stereotactic radiosurgery; TV: tumor volume; WBRT: whole brain radiotherapy
Acknowledgements The authors certify that no funding was received to conduct this study and/
or for preparation of this manuscript We are grateful to Bierta Barfod, M.D., M.P.H for her help with the language editing of this manuscript.
Funding
No funding was available for the study.
Availability of data and materials The dataset supporting the conclusions of this article is available from the corresponding author on reasonable request.
Authors ’ contributions
SY performed the radiosurgical management of these patients and prepared the manuscript MH critically reviewed the manuscript for important intellectual content Both authors have read and approved the final manuscript.
Competing interests The authors declare that they have no competing interests.
Consent for publication Not applicable because this manuscript does not contain any individual persons data.
Ethics approval and consent to participate The Institutional Review Board of Aizawa Hospital granted ethics approval to our study in October 2015 (No 2015 –038) The informed consent was waived because the study was retrospective in design.
Trang 9Received: 12 February 2016 Accepted: 5 December 2016
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